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A. S. Ibrahim, A. B. El-Remessy, S. Matragoon, G. Zhu, G. I. Liou; Activation of ERK and p38 MAPK, but not JNK, Occurs Exclusively in Retinal Microglia in Experimental Diabetes. Invest. Ophthalmol. Vis. Sci. 2009;50(13):27.
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Unravelling the pathophysiology of Diabetic Retinopathy (DR) is a unique challenge. In the disease context, neurons can be impaired indirectly through pathogenic glial loops involving the production of neurotoxic factors such as tumor necrosis factor- (TNF-) by Retinal Glial Cells (RGCs). TNF- leads to neuronal cell death, DR, and eventually blindness. Therefore, understanding the mechanism of molecular changes in retinal glial activation in response to hyperglycemic stress offers a new dimension for the development of novel therapeutic treatments for DR. It is known that MAPK cascade is one of the attractive targets for intervention in human metabolic diseases such as DR. The purpose of this study is to investigate the role of glial loops in the development of DR by determining MAPK signaling in vivo and in vitro.
Diabetes was induced in male SD rats and C57BL/6 mice by injection of STZ. Eight weeks after establishment of diabetes, eye sections or flat-mounted retinas were examined for activation of RGCs, JNK, ERK, or p38 MAPK by immunofluorescence. To further elucidate the roles of microglial activation in response to hyperglycemic stress, retinal microglial cells were isolated from newborn rats, cultured, and treated with advanced glycation end-products (AGE) in the presence or absence of JNK, ERK or p38 MAPK inhibitors. Activation of these MAPKs was determined by western analysis. TNF- levels released in the culture media were estimated by ELISA. All animal studies were conducted per the Statement for the Use of Animals in Ophthalmic and Visual Research.
Changes in morphology and antigen-expression patterns of retinal microglia were observed in diabetic rats and mice. In the diabetic retinas, both ERK and p38 MAPK were activated in microglia, but not in astrocytes or Mueller cells. In cultured microglial cells, treatment of AGE resulted in concomitant activation of ERK and p38 MAPK, followed with TNF- release.Inhibition of ERK and p38 MAPK, but not JNK activation, in AGE-treated microglial cells (by U0126, SB203580, and SP600125, respectively) resulted in significant reduction in TNF- release. All studies were conducted with n ≥ 3 with appropriate control.
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